Explore the vast range of titles available.

Bevacizumab is approved in combination with chemotherapy for the treatment of ovarian cancer, either in first-line therapy or for patients with recurrent disease not previously treated with the same drug. We aimed to test the value of continuing bevacizumab beyond progression after first-line treatment with the same drug. In our open-label, randomised, phase 3 trial done at 82 sites in four countries, we enrolled women (aged ≥18 years) who had previously received first-line platinum-based therapy including bevacizumab, and had recurrent (≥6 months since last platinum dose), International Federation of Gynaecology and Obstetrics stage IIIB–IV ovarian cancer with an Eastern Cooperative Oncology Group performance status 0–2. Patients were randomly assigned (1:1) to receive a carboplatin-based doublet intravenously (carboplatin area under the concentration curve [AUC] 5 on day 1 plus paclitaxel 175 mg/m2 on day 1, every 21 days; carboplatin AUC 4 on day 1 plus gemcitabine 1000 mg/m2 on days 1 and 8, every 21 days; or carboplatin AUC 5 on day 1 plus pegylated liposomal doxorubicin 30 mg/m2 on day 1, every 28 days), or a carboplatin-based doublet plus bevacizumab (10 mg/kg intravenous every 14 days combined with pegylated liposomal doxorubicin–carboplatin, or 15 mg/kg every 21 days combined with gemcitabine–carboplatin or paclitaxel–carboplatin). Evaluable disease according to RECIST 1.1 guidelines was required before randomisation. Randomisation was done through the trial website with a minimisation procedure, stratified by centre, time of recurrence, performance status, and type of second-line chemotherapy. The primary endpoint was investigator-assessed progression-free survival, analysed on an intention-to-treat basis. Safety was assessed in all participants who received at least one dose. This trial is registered with ClinicalTrials.gov, NCT01802749 and EudraCT 2012-004362-17. Between Dec 6, 2013, and Nov 11, 2016, 406 patients were recruited (203 [50%] assigned to the bevacizumab group and 203 [50%] to the standard chemotherapy group). 130 patients (64%) in the bevacizumab group and 131 (65%) in the standard chemotherapy group had progressed after receiving a last dose of platinum more than 12 months before, and 146 patients (72%) in the bevacizumab group and 147 (72%) in the standard chemotherapy group had progressed after completion of first-line bevacizumab maintenance. 161 participants (79%) progressed in the standard chemotherapy group, as did 143 (70%) in the bevacizumab group. Median progression-free survival was 8·8 months (95% CI 8·4–9·3) in the standard chemotherapy group and 11·8 months (10·8–12·9) in the bevacizumab group (hazard ratio 0·51, 95% CI 0·41–0·65; log-rank p<0·0001). Most common grade 3–4 adverse events were hypertension (20 [10%] in the standard chemotherapy group vs 58 (29%) in the bevacizumab group), neutrophil count decrease (81 [41%] vs 80 [40%]), and platelet count decrease (43 [22%] vs 61 [30%]). 68 patients (33%) died in the standard chemotherapy group and 79 (39%) died in the bevacizumab group; two deaths (1%) in the standard chemotherapy group and one death (<1%) in the bevacizumab group were deemed to be treatment-related. Continuing bevacizumab beyond progression combined with chemotherapy in patients with platinum-sensitive recurrent ovarian cancer improves progression-free survival compared with standard chemotherapy alone and might be considered in clinical practice. Hoffmann–La Roche and Associazione Italiana per la Ricerca sul Cancro.

BackgroundNo study has evaluated the predictive and prognostic role of CD8 and PD-L1 coexpression in non–small-cell lung cancer (NSCLC).MethodsWe analyzed RNA sequencing and/or immunohistochemistry staining in NSCLC patients from The Cancer Genome Atlas (n = 1016), and 34 metastatic NSCLC samples not treated by immunotherapy as prognostic cohorts. As predictive aspect of CD8 and PD-L1, we used 85 NSCLC patients treated with anti-PD-1. Two validation cohorts were used including 44 NSCLC patients treated with anti-PD-1 and an external cohort with different tumor types.ResultsIn prognostic cohorts, high CD8A expression was associated with longer OS (p = 0.02), while high CD274 mRNA was associated with poor prognosis (p = 0.05). In predictive cohort, high CD8 expression and CD8A mRNA were associated with longer progression-free survival (PFS) (p = 0.0002). There was no significant association between PD-L1 expression and PFS while high CD274 mRNA was associated with longer PFS (p = 0.009). A combination of CD8A and CD274 was highly predictive of outcome. These results were confirmed in the validation cohorts. This two-genes signature demonstrated similar results compared to gold standard signatures.ConclusionCD8 represents both a prognostic and predictive factor of outcomes, while PD-L1 share different prognostic and predictive roles.

Understanding the processes of inflammation and tissue regeneration after injury is of great importance. For a long time, macrophages have been known to play a central role during different stages of inflammation and tissue regeneration. However, the molecular and cellular mechanisms by which they exert their effects are as yet mostly unknown. While in vitro macrophages have been characterized, recent progress in macrophage biology studies revealed that macrophages in vivo exhibited distinctive features. Actually, the precise characterization of the macrophages in vivo is essential to develop new healing treatments and can be approached via in situ analyses. Nowadays, the characterization of macrophages in situ has improved significantly using antigen surface markers and cytokine secretion identification resulting in specific patterns. This review aims for a comprehensive overview of different tools used for in situ macrophage identification, reporter genes, immunolabeling and in situ hybridization, discussing their advantages and limitations.

BackgroundCheckpoint inhibitors (CKI) targeting PD-1 or PD-L1 are major therapies for the treatment of non-small cell lung cancer (NSCLC). Despite numerous studies of biological biomarkers, we currently lack a marker to predict CKI primary resistance. The aim of this study was to isolate clinical markers associated with the absence of efficacy of CKI used as monotherapy in NSCLC.MethodsWe conducted a retrospective analysis of 172 patients treated with anti-PD1 or anti-PDL1 monoclonal antibodies (mAb) for advanced NSCLC at the Dijon Cancer Center. Baseline characteristics were compared using the Chi squared test between responders and non-responders. Survival curves were estimated by the Kaplan–Meier method and compared with the Log-rank test for univariate analysis. Cox regression models were used to determine hazard ratios and 95% confidence intervals for progression-free survival (PFS) and overall survival (OS).ResultsAmong 172 patients included, 149 (86.5%) received CKI after platinum chemotherapy. Response rate (RR) was 16%, median progression-free survival (PFS) was 2.5 months (95% CI 0.7–30 months) and median overall survival (OS) was 10 months (95% CI 0.7–46.8 months). By univariate analysis, WHO performance status ≥ 1, presence of bone, liver and pleuroperitoneal metastasis were associated with poor PFS and OS. Multivariate analysis showed that only pleuroperitoneal metastasis was independently associated with PFS and OS. Patients with pleuroperitoneal metastasis and WHO performance status ≥ 1 had a < 10% chance of yielding a benefit from CKI.ConclusionsOur data support the hypothesis that pleuroperitoneal metastasis is a major predictive factor affecting CKI efficacy in NSCLC patients and may be used to avoid CKI monotherapy for such patients.

Producing industrially significant compounds with more environmentally friendly represents a challenging task. The large-scale production of an exogenous molecule in a host microfactory can quickly cause toxic effects, forcing the cell to inhibit production to survive. The key point to counter these toxic effects is to promote a gain of tolerance in the host, for instance, by inducing a constant flux of the neo-synthetized compound out of the producing cells. Efflux pumps are membrane proteins that constitute the most powerful mechanism to release molecules out of cells. We propose here a new biological model, Deinococcus geothermalis , organism known for its ability to survive hostile environment; with the aim of coupling the promising industrial potential of this species with that of heterologous efflux pumps to promote engineering tolerance. In this study, clones of D. geothermalis containing various genes encoding chromosomal heterologous efflux pumps were generated. Resistant recombinants were selected using antibiotic susceptibility tests to screen promising candidates. We then developed a method to determine the efflux efficiency of the best candidate, which contains the gene encoding the MdfA of Salmonella enterica serovar Choleraesuis. We observe 1.6 times more compound in the external medium of the hit recombinant than that of the WT at early incubation time. The data presented here will contribute to better understanding of the parameters required for efficient production in D. geothermalis .

Background Ovarian cancer (OC) remains one of the most challenging and deadly malignancies facing women today. While PARP inhibitors (PARPis) have transformed the treatment landscape for women with advanced OC, many patients will relapse and the PARPi-resistant setting is an area of unmet medical need. Traditional immunotherapies targeting PD-1/PD-L1 have failed to show any benefit in OC. The CD47/TSP-1 axis may be relevant in OC. We aimed to describe changes in CD47 expression with platinum therapy and their relationship with immune features and prognosis. Methods Tumor and blood samples collected from OC patients in the CHIVA trial were assessed for CD47 and TSP-1 before and after neoadjuvant chemotherapy (NACT) and multiplex analysis was used to investigate immune markers. Considering the therapeutic relevance of targeting the CD47/TSP-1 axis, we used the CD47-derived TAX2 peptide to selectively antagonize it in a preclinical model of aggressive ovarian carcinoma. Results Significant reductions in CD47 expression were observed post NACT. Tumor patients having the highest CD47 expression profile at baseline showed the greatest CD4 + and CD8 + T-cell influx post NACT and displayed a better prognosis. In addition, TSP-1 plasma levels decreased significantly under NACT, and high TSP-1 was associated with a worse prognosis. We demonstrated that TAX2 exhibited a selective and favorable biodistribution profile in mice, localizing at the tumor sites. Using a relevant peritoneal carcinomatosis model displaying PARPi resistance, we demonstrated that post-olaparib (post-PARPi) administration of TAX2 significantly reduced tumor burden and prolonged survival. Remarkably, TAX2 used sequentially was also able to increase animal survival even under treatment conditions allowing olaparib efficacy. Conclusions Our study thus (1) proposes a CD47-based stratification of patients who may be most likely to benefit from postoperative immunotherapy, and (2) suggests that TAX2 is a potential alternative therapy for patients relapsing on PARP inhibitors.

Cytokines secreted by individual immune cells regulate tissue regeneration and allow communication between various cell types. Cytokines bind to cognate receptors and trigger the healing process. Determining the orchestration of cytokine interactions with their receptors on their cellular targets is essential to fully understanding the process of inflammation and tissue regeneration. To this end, we have investigated the interactions of Interleukin-4 cytokine (IL-4)/Interleukin-4 cytokine receptor (IL-4R) and Interleukin-10 cytokine (IL-10)/Interleukin-10 cytokine receptor (IL-10R) using in situ Proximity Ligation Assays in a regenerative model of skin, muscle and lung tissues in the mini-pig. The pattern of protein–protein interactions was distinct for the two cytokines. IL-4 bound predominantly to receptors on macrophages and endothelial cells around the blood vessels while the target cells of IL-10 were mainly receptors on muscle cells. Our results show that in situ studies of cytokine–receptor interactions can unravel the fine details of the mechanism of action of cytokines.

Melioidosis is an endemic disease in southeast Asia and northern Australia caused by the saprophytic bacteria Burkholderia pseudomallei, with a high mortality rate. The clinical presentation is multifaceted, with symptoms ranging from acute septicemia to multiple chronic abscesses. Here, we report a chronic case of melioidosis in a patient who lived in Malaysia in the 70s and was suspected of contracting tuberculosis. Approximately 40 years later, in 2014, he was diagnosed with pauci-symptomatic melioidosis during a routine examination. Four strains were isolated from a single sample. They showed divergent morphotypes and divergent antibiotic susceptibility, with some strains showing resistance to trimethoprim-sulfamethoxazole and fluoroquinolones. In 2016, clinical samples were still positive for B. pseudomallei, and only one type of strain, showing atypical resistance to meropenem, was isolated. We performed whole genome sequencing and RT-qPCR analysis on the strains isolated during this study to gain further insights into their differences. We thus identified two types of resistance mechanisms in these clinical strains. The first one was an adaptive and transient mechanism that disappeared during the course of laboratory sub-cultures; the second was a mutation in the efflux pump regulator amrR, associated with the overexpression of the related transporter. The development of such mechanisms may have a clinical impact on antibiotic treatment. Indeed, their transient nature could lead to an undiagnosed resistance. Efflux overexpression due to mutation leads to an important multiple resistance, reducing the effectiveness of antibiotics during treatment.

Over the past 70 years, significant progress has been made in understanding the molecular and cellular mechanisms of inflammation and tissue regeneration [...].Over the past 70 years, significant progress has been made in understanding the molecular and cellular mechanisms of inflammation and tissue regeneration [...].

Background With the growing number of older endometrial cancer (EC) and ovarian cancer (OC) survivors, data on long-term health-related quality of life (HRQoL) became an important issue in the management of older patients. So, the aim of this study was to describe and compare according to age long-term HRQoL, sexual function, and social deprivation of adults with either EC or OC. Methods A cross-sectional study was set up using data from the Côte d’Or gynecological cancer registry. A series of questionnaires assessing HRQoL (SF-12), sexual function (FSFI), anxiety/depression (HADS), social support (SSQ6) and deprivation (EPICES) were offered to women with EC or OC diagnosed between 2006 and 2013. HRQoL, sexual function, anxiety/depression, social support and deprivation scores were generated and compared according to age (< 70 years and ≥ 70 years). Results A total of 145 women with EC (N = 103) and OC (N = 42) participated in this study. Fifty-six percent and 38% of EC and OC survivors respectively were aged 70 and over. Treatment did not differ according to age either in OC or EC. The deprivation level did not differ between older and younger survivors with OC while older survivors with EC were more precarious. The physical HRQoL was more altered in older EC survivors. This deterioration concerned only physical functioning (MD = 24, p  = 0.012) for OC survivors while it concerned physical functioning (MD = 30, p  < 0.0001), role physical (MD = 22, p  = 0.001) and bodily pain (MD = 21, p  = 0.001) for EC survivors. Global health (MD = 11, p  = 0.011) and role emotional (MD = 12, p  = 0.018) were also deteriorated in elderly EC survivors. Sexual function was deteriorated regardless of age and cancer location with a more pronounced deterioration in elderly EC survivors for desire ( p  = 0.005), arousal ( p  = 0.015) and orgasm ( p  = 0.007). Social support, anxiety and depression were not affected by age regardless of location. Conclusion An average 6 years after diagnosis, the impact of cancer on HRQoL is greatest in elderly survivors with either EC or OC.